Real world clinical outcomes with trastuzumab deruxtecan in HER2 expressing ovarian and endometrial cancer

Background : Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, is an FDA-approved treatment option for HER2-expressing (IHC 2+/3+) recurrent endometrial (EC) and ovarian cancers (OC) based on DESTINY-PanTumor02. Real-world evidence remains limited. Methods: We conducted a retrospective study of all patients with recurrent or metastatic OC or EC who received T-DXd between September 2022 and November 2025 at a single academic medical center. Primary endpoints were real-world objective response rate (ORR), disease control rate (DCR; by radiology reports) and median time on treatment (mTOT). Secondary endpoints were median progression-free survival (mPFS), and overall survival (mOS), estimated by Kaplan-Meier. Results : Thirty-three patients received T-DXd (17 OC, 16 EC, Table 1). The ORR and DCR were 42.4% (14/33) and 66% (22/33), including 4 complete responses and 6 partial responses. The mTOT was 5.5 months (mos) (IQR 1.4-7.6). ORR by HER2 IHC score was 83% for 3+, 42% for 2+, and 0% for 1+. Patients with IHC 1+ had a DCR of 100% and mTOT of 7.3 mos (IQR 2.8-18.6). ORR was 69% in patients with ≤2 prior lines (n=13) and 0% among those with prior topoisomerase-1 inhibitor (topotecan) exposure (n=3) or in BRCA-mutated tumors (n=4). Patients with prior mirvetuximab (n=7) had an ORR of 14% and DCR of 71%.By tumor type: ORR was 47% in OC and 38% in EC; DCR was 76% in OC and 56% in EC; mTOT was 5.5 mos (2.5-9.0) in OC and 4.7 mos (0.8-6.9) in EC. The mPFS was 6.2 mos (95% CI 2.3-15.8) for OC and 6.0 mos (1.4-7.6) for EC. mOS from T-DXd start was 17.3 mos (11.4-27.6) for OC and 10.4 mos (6.3-NR) for EC. Conclusion : In this real-world cohort, T-DXd demonstrated promising outcomes consistent with DESTINY-PanTumor02. High response rates were observed in IHC 3+ tumors and earlier-line use, while no responses were seen with prior topoisomerase-1 inhibitor exposure or in BRCA-mutated cases. Further studies are needed to validate predictors of response and optimize treatment sequencing. Baseline Characteristics *HER2 amp by FISH or next generation sequencing. **3 germline, 1 somatic. Ovarian cancer N = 17 Endometrial cancer N = 16 Age at diagnosis, mean (std dev) 60.8 (7.6) 66.9 (6.1) Histology, n (%) Serous 13 (76%) 8 (50%) Clear cell 2 (12%) 1 (6%) Carcinosarcoma 0 3 (18%) Endometrioid 1 (6%) 4 (25%) Other 1 (6%) 0 Lines of treatment prior to T-DXd, median (interquartile range/IQR) 4 (2.5-6.5) 2 (2-3) Total lines of treatment, median (IQR) 5 (4-9.5) 4 (3-4.8) HER2 expression 1+ 4 (23%) 1 (6%) 2+ 9 (53%) 12 (75%) 3+ 3 (18%) 3 (18%) Amplification* 7 (41%) 6 (37%) BRCA-mutated** 2 (12%) 2 (12%) Homologous recombination deficient (HRD)+ 5 (29%) 2 (12%) Prior topoisomerase-1 inhibitor 3 (17%) 0 Prior poly(ADP-ribose) polymerase inhibitor (PARP) 7 (41%) 1 (6%) Prior ADC 7 (41%) 2 (12%) Endometrial subgroup Deficient mismatch repair (dMMR) - 1 (6%) No specific molecular profile (NSMP) - 1 (6%) TP53-mutated - 14 (88%) POLE-mutated - 0